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Ritchie T.J.,TJR Chemical | MacDonald S.J.F.,Glaxosmithkline | Peace S.,Glaxosmithkline | Pickett S.D.,Glaxosmithkline | Luscombe C.N.,Glaxosmithkline
MedChemComm | Year: 2012

Aqueous solubility, protein binding and CYP450 inhibition data for compounds containing a variety of heteroaromatic and heteroaliphatic rings were analysed and compared to determine which ring types fared best and worst in these developability screens. The results suggest that certain heterorings are generally more developable than others: how this information may be used and some caveats to be borne in mind are discussed. © 2012 The Royal Society of Chemistry.


Ritchie T.J.,TJR Chemical | Macdonald S.J.F.,Glaxosmithkline
Journal of Medicinal Chemistry | Year: 2014

Published physicochemical descriptors of molecules that convey aromaticity-related character are reviewed in the context of drug design and discovery. Studies that have employed aromatic descriptors are discussed, and several descriptors are compared and contrasted. © 2014 American Chemical Society.


Ritchie T.J.,TJR Chemical | Macdonald S.J.F.,Glaxosmithkline
Drug Discovery Today | Year: 2014

Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring drugs were compared to determine how well the score correlated with their actual pharmaceutical and pharmacokinetic (PK) profiles in humans. Drugs with high QED scores exhibit higher absorption and bioavailability, are administered at lower doses and have fewer drug-drug interaction warnings, P-glycoprotein interactions and absorption issues due to a food effect. By contrast, the high-scoring drugs exhibit similar behaviour to low-scoring drugs with respect to free fraction in plasma, extent of gut-wall metabolism, first-pass hepatic extraction, elimination half-life, clearance, volume of distribution and frequency of dosing. © 2014 Elsevier Ltd.


Ritchie T.J.,TJR Chemical | Macdonald S.J.F.,Glaxosmithkline | Pickett S.D.,Glaxosmithkline
MedChemComm | Year: 2015

The impact of N- and O-methylation on chromatographically measured lipophilicity and high throughput chemiluminescent nitrogen detection (CLND) aqueous solubility was studied using matched molecular pairs for data sets of amides, sulfonamides, ureas, carbamates, amines, carboxylic acids, alcohols and phenols. The extent to which solubility and lipophilicity are affected by N- or O-methylation is dependent on the nature of atoms and substituents around the nitrogen or oxygen atom. In some classes of amides, N-methylation unexpectedly increases solubility and lowers logD7.4 considerably: this behaviour can be rationalised by conformational changes accompanying N-methylation that increase polar surface area, or by the disruption of one or more intramolecular hydrogen bonding motifs. Unlike amides, sulfonamide N-methylation always reduces solubility and increases lipophilicity, which again can be understood in terms of conformational effects. As expected, methylation of carboxylic acids lowers solubility and increases lipophilicity due to masking of the ionisable acidic group; however the magnitude of the reduction in solubility depends to some extent on the lipophilicity and molecular weight of the compound pairs under investigation. © The Royal Society of Chemistry 2015.


Ritchie T.J.,TJR Chemical | MacDonald S.J.F.,Glaxosmithkline | Peace S.,Glaxosmithkline | Pickett S.D.,Glaxosmithkline | Luscombe C.N.,Glaxosmithkline
MedChemComm | Year: 2013

Using compounds occupying four distinct clog P/molecular weight regions that define optimal and sub-optimal chemical space, and a developability score derived from solubility, permeability, protein binding and 3A4 inhibition screening data, OPLS regression models were constructed to determine which physico-chemical properties were most correlated with developability. The results suggested that whilst certain molecule properties were important for developability across all chemical space, such as [clog D + aromatic ring count], [clog D + (aromatic atom count-sp3 carbon count)] and [sp3 carbon count/total carbon count], others such as heteroaliphatic ring count, positive ionisable group count and H-bond donor character exhibited varying degrees of importance depending on the clog P/Mw region. © 2013 The Royal Society of Chemistry.


PubMed | TJR Chemical
Type: Journal Article | Journal: Drug discovery today | Year: 2011

The importance of striving for and maintaining drug-like physicochemical properties during the hit and lead optimization process is now well documented, and many published studies have suggested optimal ranges and/or limits for key molecule descriptors such as size, lipophilicity, H-bonding characteristics, rotatable bond and aromatic ring counts, particularly with regard to the design of orally administered drugs. The aim of this article is to review various approaches that have been used to represent molecule properties graphically in the context of oral drug likeness, with the goal of improving the decision making of medicinal chemists during the drug discovery process.


PubMed | Glaxosmithkline and TJR Chemical
Type: | Journal: European journal of medicinal chemistry | Year: 2016

The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities.

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